US20080275131A1 - Compositions of (-)-e-10-oh-nt and methods for their synthesis and use - Google Patents

Compositions of (-)-e-10-oh-nt and methods for their synthesis and use Download PDF

Info

Publication number
US20080275131A1
US20080275131A1 US12/107,742 US10774208A US2008275131A1 US 20080275131 A1 US20080275131 A1 US 20080275131A1 US 10774208 A US10774208 A US 10774208A US 2008275131 A1 US2008275131 A1 US 2008275131A1
Authority
US
United States
Prior art keywords
disorders
pain
enantiomerically pure
salt
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/107,742
Other languages
English (en)
Inventor
Bertrand Le Bourdonnec
Roland E. Dolle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adolor Corp
Original Assignee
Adolor Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adolor Corp filed Critical Adolor Corp
Priority to US12/107,742 priority Critical patent/US20080275131A1/en
Assigned to ADOLOR CORPORATION reassignment ADOLOR CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DOLLE, ROLAND E., LE BOURDONNEC, BERTRAND
Publication of US20080275131A1 publication Critical patent/US20080275131A1/en
Priority to US13/427,744 priority patent/US20120178815A1/en
Assigned to ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT reassignment ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT SECURITY AGREEMENT Assignors: ADOLOR CORPORATION, CALIXA THERAPEUTICS, INC., CUBIST PHARMACEUTICALS HOLDINGS, INC., CUBIST PHARMACEUTICALS U.S., CUBIST PHARMACEUTICALS, INC.
Assigned to CUBIST PHARMACEUTICALS, INC., CALIXA THERAPEUTICS, INC., ADOLOR CORPORATION reassignment CUBIST PHARMACEUTICALS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • Tricyclic antidepressants including amitriptyline (AT) and nortryptiline (NT), have been shown to inhibit the reuptake of monoamines, including norepinephrine and serotonin, and have been widely used both on and off label to treat many different disorders and diseases mediated, at least in part, by dysregulated uptake or reuptake of norepinephrine and serotonin, including, but not limited to, mood disorders such as depression, anxiety disorders such as obsessive compulsive disorder (OCD), eating disorders such as anorexia nervosa and bulimia nervosa, impulse-control disorders such as tricholtillomania, sleep disorders such as insomnia related to opioid withdrawal, personality disorders such as attention deficit hyperactivity disorder (ADHD) and somatoform disorders such as certain types of pain.
  • ADHD attention deficit hyperactivity disorder
  • AT and NT have also been used as first-line treatment for various types of acute and chronic pain that are either nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin, including non-nociceptive neuropathic pains such as diabetic neuropathy and post herpetic neuralgia (PHN), and nociceptive pain including inflammatory pain and interstitial cystitis.
  • nociceptive for example somatic or visceral
  • non-nociceptive for example neuropathic or sympathetic
  • non-nociceptive neuropathic pains such as diabetic neuropathy and post herpetic neuralgia (PHN)
  • PPN post herpetic neuralgia
  • nociceptive pain including inflammatory pain and interstitial cystitis.
  • AT and NT have been limited by their untoward side effects, which include, but are not limited to, antimuscarinic effects such as dry mouth, constipation, nausea and urinary retention; headaches, increased sweating, tinnitus, unpleasant taste, cardiotoxic effects such as orthostatic hypotension, arrhythmias, and tachycardia; sedation and weight gain.
  • NT and AT are also contraindicated for use with various mediations due to shared side effects and/or the interaction of NT and AT with the cytochrome P450 drug metabolizing enzymes.
  • amitriptyline (“AT”) and nortriptyline (“NT”) share a number of common metabolites, the major one of which is [(5-[3-methylamino-propylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol] (“10-OH-NT”).
  • This 10-OH-NT metabolite has two geometric isomers depending upon the configuration about the double bond (Z-10-OH-NT and E-10-OH-NT).
  • Each of these geometric isomers comprises two enantiomers, (+)-E-10-OH-NT, and ( ⁇ )-E-10-OH-NT, and (+)-Z-10-OH-NT and ( ⁇ )-Z-10-OH-NT, owing to chirality at the carbon at the 10-position.
  • Certain studies suggest that the racemate of the major 10-OH-NT metabolite, ( ⁇ )-E-10-OH-NT, might be useful to treat depression and anxiety when administered orally to humans (Nordin et al., 1987a).
  • ( ⁇ )-E-10-OH-NT binds norepinephrine (“NE”) and serotonin (“5HT”) monoamine transporters and inhibits uptake of NE and 5HT, biological activities known to be associated with the antidepressant and other therapeutic properties of AT and NT.
  • NE norepinephrine
  • 5HT serotonin
  • ( ⁇ )-E-10-OH-NT does not share in common with AT and NT certain pharmacological and biochemical properties that correlate with untoward side effects during use.
  • AT and NT potently antagonize the H 1 histaminergic receptor, a property that plays a role in the significant weight gain (Altamura et al., 1989; Wirshing et al., 1999; Richelson, 2001; Khawam et al., 2006) and undesirable sedative effects (Bryson & Wilde, 1996) observed with both short and long term use of AT and NT, ( ⁇ )-E-10-OH-NT antagonizes the H 1 histaminergic receptor to a much lesser extent.
  • ( ⁇ )-E-10-OH-NT offers therapeutic benefits that are unprecedented in the art for tricyclic antidepressant drugs. Because ( ⁇ )-E-10-OH-NT shares therapeutically relevant pharmacological and biochemical properties with AT and NT, it can be used, either in substantially enantiomerically pure or enantiomerically pure form to treat the many indications commonly treated with AT and NT, including but not limited to the various diseases and disorders mentioned further herein. However, because ( ⁇ )-E-10-OH-NT does not possess certain pharmacological and biochemical properties known to be responsible for untoward side effects, therapy can be administered to patients with a lower incidence of undesirable side effects.
  • ( ⁇ )-E-10-OH-NT is a significantly less potent H 1 histaminergic receptor antagonist than AT and NT, therapeutic benefit can be achieved with this agent without the undesirable side effects of significant weight gain and sedation experienced with AT and/or NT therapy.
  • racemic ( ⁇ )-E-10-OH-NT and its (+) enantiomer also possess important and approximately equipotent biochemical activities in in vitro assays.
  • ( ⁇ )-E-10-OH-NT, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT each exhibit approximately equal affinities for the norepinephrine transporter and also the serotonin transporter (see Example 14).
  • the (+) and ( ⁇ ) enantiomers of E-10-OH-NT exhibit approximately equipotent selective inhibition of norepinephrine uptake, and are approximately equipotent to AT in functional in vitro assays (see Example 5).
  • the present disclosure provides compositions comprising E-10-OH-NT and optionally one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the E-10-OH-NT is present in the composition as non-racemic mixture enriched in the ( ⁇ ) enantiomer.
  • the E-10-OH-NT comprising the composition is substantially enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the E-10-OH-NT comprising the composition is enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the E-10-OH-NT can be present in the composition in the form of the free base, or in the form of a salt. In some embodiments, the E-10-OH-NT is present in the form of a pharmaceutically acceptable acid addition salt.
  • the E-10-OH-NT (including salt forms) can also be present in the composition in the form of a solvate and/or hydrate, for example with solvents and/or water used during preparation or purification.
  • the E-10-OH-NT composition can be used in vitro or in vivo, as will be described in more detail below.
  • the composition can be formulated for administration to animals in veterinary contexts, or for administration to humans via virtually any route or mode of administration, including but not limited to, oral, topical, ocular, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, inhalation or insufflation.
  • the present disclosure provides methods of treating diseases or indications responsive to AT or NT therapy.
  • the methods generally comprise administering to a mammal, including a human, suffering from a disease or indication responsive to treatment with AT or NT, an amount of a composition described herein effective to treat the disease or indication.
  • the E-10-OH-NT composition comprises E-10-OH-NT that is enriched in the ( ⁇ ) enantiomer. In some embodiments, the E-10-OH-NT composition comprises substantially enantiomerically pure ( ⁇ )-E-10-OH-NT. In some embodiments the E-10-OH-NT composition comprises enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • DSM-IV Diagnostic and Statistic Manual of Mental Disorders IV
  • mood disorders such as, for example, depression
  • anxiety disorders such as, for example OCD
  • eating disorders such as, for example, anorexia nervosa and bulimia nervosa
  • impulse disorders such as, for example, trichotillomania
  • sleep disorders such as, for example, insomnia related to opioid withdrawal
  • personality disorders such as, for example, ADHD
  • somatoform disorders such as certain types of pain
  • Another important class of diseases or indications known to be responsive to treatment with AT and/or NT is pain, including both acute and chronic pain, whether nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin (discussed further below).
  • nociceptive for example somatic or visceral
  • non-nociceptive for example neuropathic or sympathetic
  • the E-10-OH-NT compositions can be used alone as monotherapy, or, alternatively, they can be used in combination with, or adjunctively to, other treatments.
  • the E-10-OH-NT composition may be administered in combination with, or adjunctively to, another therapeutic agent useful to treat the same mental disease or indication.
  • the E-10-OH-NT composition may be administered in combination with, or adjunctively to, another therapeutic agent useful to treat the same type of pain.
  • such combination or adjunctive therapies are not limited to combinations of compounds useful to treat the same indication.
  • the E-10-OH-NT composition may be useful or desirable to administer the E-10-OH-NT composition in combination with, or adjunctively to, therapeutic agents that do not treat the disease or disorder being treated with the E-10-OH-NT composition.
  • the E-10-OH-NT composition to be administered in combination with, or adjunctively to, other treatments comprises E-10-OH-NT that is enriched in the ( ⁇ ) enantiomer.
  • the E-10-OH-NT composition comprises substantially enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the E-10-OH-NT composition comprises enantiomerically pure ( ⁇ )-E-10-OH-NT. Representative non-limiting examples of suitable combinations are discussed in more detail in a later section.
  • the present disclosure provides methods of inhibiting uptake of NE and/or 5HT.
  • the methods generally comprise contacting a NE and/or 5HT transporter with an amount of ( ⁇ )-E-10-OH-NT effective to inhibit uptake of NE and/or 5HT.
  • the method is carried out in the absence of AT and NT.
  • the NE and/or 5HT transporter is contacted with an E-10-OH-NT composition as described herein.
  • the E-10-OH-NT composition comprises E-10-OH-NT that is enriched in the ( ⁇ ) enantiomer. In some embodiments, the E-10-OH-NT composition comprises substantially enantiomerically pure ( ⁇ )-E-10-OH-NT. In some embodiments, the E-10-OH-NT composition comprises enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the methods can be practiced in vitro with isolated transporters or cells that express one or both transporters, or in vivo as a therapeutic approach towards the treatment of diseases or disorders that are, at least in part, mediated by dysregulated uptake or reuptake of NE and/or 5HT.
  • diseases or disorders that are, at least in part, mediated by dysregulated uptake or reuptake of NE and/or 5HT include, but are not limited to, those listed above.
  • antidepressants including those that inhibit reuptake of NE (NRIs) and/or 5HT (SRIs) have been used as a first-line therapy for treating both acute and chronic pain that is either nociceptive or non-nociceptive in origin, for example, neuropathy, post-herpetic neuralgia (PHN), pain associated with fibromyalgia, pain associated with irritable bowel syndrome and interstitial cystitis (Sindrup & Jensen, 1999; Collins et al., 2000; Crowell et al., 2004).
  • PDN post-herpetic neuralgia
  • a recent study systematically evaluated the relative activity at the NE and/or 5HT transporter required for maximal efficacy in rodent models of pain (Leventhal et al., 2007).
  • duloxetine a dual SRI and NRI with potency at both 5HT and NE transporters, was the first reuptake inhibitor approved for the treatment of diabetic neuropathy (Bymaster et al., 2005; Goldstein et al., 2005).
  • ( ⁇ )-E-10-OH-NT makes this compound ideally suited for the treatment of many different types of pain syndromes. Indeed, in experiments carried out by the applicants and reported herein, ( ⁇ )-E-10-OH-NT exhibited robust therapeutic efficacy in rodent models of both nociceptive inflammatory pain (see Examples 6, 15 and 16) and non-nociceptive neuropathic pain (see Examples 5 and 17-20) pain. In both models, the efficacy observed for ( ⁇ )-E-10-OH-NT was equivalent to that of AT.
  • the present disclosure provides methods of treating pain in mammals, including humans.
  • the methods generally comprise administering to a mammal suffering from pain, including a human, an amount of an E-10-OH-NT composition described herein effective to treat the pain.
  • the E-10-OH-NT composition comprises E-10-OH-NT that is enantiomerically enriched in ( ⁇ ) enantiomer.
  • the E-10-OH-NT composition comprises substantially enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the composition comprises enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the methods can be used to treat numerous different types of pain syndromes, including acute or chronic pain that is either nociceptive in origin (for example somatic or visceral) or non-nociceptive in origin (for example neuropathic or sympathetic).
  • the pain is nociceptive pain including, but not limited to, inflammatory pain such as that associated with IBS or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis.
  • the pain is non-nociceptive pain including, but not limited to, neuropathic pain such as post-herpetic neuralgia (PHN), trigeminal neuralgia, focal peripheral nerve injury, anesthesia clolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • neuropathic pain such as post-herpetic neuralgia (PHN), trigeminal neuralgia, focal peripheral nerve injury, anesthesia clolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • PPN post-herpetic neuralgia
  • trigeminal neuralgia focal peripheral nerve injury
  • anesthesia clolorosa anesthesia clolorosa
  • central pain
  • the E-10-OH-NT composition can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating pain and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the E-10-OH-NT compositions in a pain treatment or management regimen are provided in a later section.
  • the E-10-OH-NT compositions described herein are expected to provide significant advantages over drugs currently used to treat and/or manage pain, and in particular neuropathic pain syndromes. Most common tricyclic antidepressants used for treating pain antagonize the H 1 histaminergic receptor, and are therefore associated with significant weight gain and sedative effects. As mentioned above, ( ⁇ )-E-10-OH-NT antagonizes this receptor to a significantly lesser extent, and has proven to not induce sedation in a rodent model of sedation at doses of ( ⁇ )-E-10-OH-NT demonstrated herein to be effective in vivo in treating both nociceptive inflammatory and non-nociceptive neuropathic pain. Thus, the E-10-OH-NT compositions described herein provide a means of treating or managing pain while minimizing weight gain and sedation.
  • E-10-OH-NT compositions described herein are expected to provide additional significant advantages when used to treat pain, or any of the other many diseases and indications described herein.
  • AT and NT are known inhibitors of cytochrome P 450 isoenzymes CYP2D6 and CYP2C19, and as a consequence are contraindicated for use with several important drugs metabolized by these enzymes.
  • Exemplary drugs that are known to be metabolized at least in part by CYP2D6, and may therefore be contraindicated for use with AT and NT include S-metoprolol, propafenone, timolol, clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, aripiprazole, codeine, dextromethorphan, duloxetine, flecainide, mexiletine, ondansetron, tamoxifen, tramadol and venlafaxine.
  • Exemplary drugs that are known to be metabolized at least in part by CYP2C19, and may therefore be contraindicated for use with AT and NT include omeprazole, lansoprazole, pantoprazole, rabeprazole, diazepam, phenyloin, phenobarbitone, clomipramine, cyclophosphamide and progesterone.
  • Data obtained by the present applicants and reported herein demonstrate that ( ⁇ )-E-10-OH-NT is a less potent inhibitor of both CYP2C19 and CYP2D6 than AT and NT.
  • E-10-OH-NT compositions described herein would engender fewer undesirable clinical consequences than AT and/or NT therapy, especially when used in combination with, or adjunctively to, drugs that are metabolized at least in part by these cytochrome P450 isoenzymes.
  • ( ⁇ )-E-10-OH-NT has a significantly lower affinity for muscarinic receptors than AT and NT, exhibits a lower inhibition of human Ether-a-Go-go related gene (hERG) potassium channels than AT and NT, and is less antagonistic at adrenergic receptors, including both ⁇ 1 , and ⁇ 2 adrenergic receptors, than AT and NT. All of these properties are expected to result in improved clinical benefits as compared to AT and NT therapy. For example, inhibition of muscarinic receptors has been linked to dry mouth, constipation and blurred vision.
  • hERG human Ether-a-Go-go related gene
  • Agonists of the ⁇ 2 adrenergic receptors have been reported to produce analgesia (Ongioco et al., 2000; Asano et al., 2000; Hall et al., 2001), while antagonists inhibit these analgesic effects (Kalso et al., 1991; Millan & Colpaert 1991; Petrovaara et al., 1990). While not intending to be bound by any theory of operation, it is expected that patients treated with the E-10-OH-NT compositions described herein will exhibit fewer undesirable side effects than patients treated with AT and/or NT.
  • ( ⁇ )-E-10-OH-NT does not antagonize ⁇ 2 adrenergic receptors. Therefore, in theory, the E-10-OH-NT compositions described herein are also expected to be superior to AT and NT in the treatment of pain. Indeed, as illustrated in FIGS. 3 & 4 , ( ⁇ )-E-10-OH-NT proved superior to AT in rodent models of both nociceptive and non-nociceptive pain.
  • the present disclosure provides chiral-specific methods of synthesizing (+) and ( ⁇ ) enantiomers of E-10-OH-NT, intermediates useful for the methods, and chiral specific methods of synthesizing the intermediates.
  • intermediates useful for the chiral-specific synthesis of (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT are (+) and ( ⁇ ) enantiomers of E-5-( ⁇ -bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene, respectively, illustrated as compounds (+)-7 and ( ⁇ )-7, respectively, in FIG. 1A .
  • the absolute configuration of the chiral 10-carbon of the (+) and ( ⁇ ) enantiomers of compounds 7 have not been established directly. Accordingly, the bond connecting the hydroxyl group to this chiral carbon atom (chirality is indicated with an asterisk) is illustrated with unspecified stereochemistry.
  • the chirality of compounds 7 may be inferred from the absolute stereochemistry of ( ⁇ )-E-10-OH NT (depicted in FIG. 6 ), which has been determined by X-ray crystallographic analysis of the malate salt of ( ⁇ )-E-10-OH NT.
  • Methods of synthesizing chiral intermediates (+)-7 and ( ⁇ )-7 generally comprise reducing E-5-( ⁇ -bromopropylidene)-10,11-dihydro-10-oxo-5H-dibenzo[a,d]-cycloheptene (illustrated as compound 6 in FIG. 1A ) in the presence of a chiral-specific oxazaborolidine catalyst.
  • a chiral-specific oxazaborolidine catalyst Non-limiting exemplary embodiments of suitable chiral-specific oxazaborolidine catalysts are illustrated in FIG. 1B .
  • the chiral-specific oxazaborolidine catalyst is (7 ⁇ S)-3-methyl-1,1-diphenylperhydro-3-bora-2-oxapyrrolizine (“7 ⁇ S-CBS”; compound S-10 in FIG. 1A ), yielding ( ⁇ )-7.
  • the chiral-specific oxazaborolidine catalyst is (7 ⁇ R)-3-methyl-1,1-diphenylperhydro-3-bora-2-oxapyrrolizine (“7 ⁇ R-CBS”; compound R-10 in FIG. 1B ), yielding (+)-7.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT can be synthesized from intermediates (+)-7 and ( ⁇ )-7, respectively, by reacting the intermediates with methylamine.
  • a specific embodiment of the synthesis utilizing CBS as the chiral-specific catalyst is illustrated in FIG. 1A . Utilizing this scheme under the reaction conditions provided in the Examples section, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT can be readily synthesized in high yield with an enantiomeric purity of greater than 99%.
  • FIG. 1A provides an exemplary scheme that can be used to synthesize enantiomerically pure (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT;
  • FIG. 1B provides exemplary embodiments of chiral-specific oxazaborolidine catalysts that can be used in the synthetic scheme illustrated in FIG. 1A ;
  • FIG. 2 provides a graph demonstrating the non-sedative effects of ( ⁇ )-E-10-OH-NT as compared to AT and NT in the rat rotarod model of sedation;
  • FIG. 3 provides a graph demonstrating the superior antihyperalgesic efficacy of ( ⁇ )-E-10-OH-NT as compared to AT in a rodent model of nociceptive inflammatory pain;
  • FIG. 4 provides a graph demonstrating the superior antiallodynic efficacy of ( ⁇ )-E-10-OH-NT as compared to AT in a rodent model of non-nociceptive neuropathic pain;
  • FIG. 5 provides a graph demonstrating the superior properties of ( ⁇ )-E-10-OH-NT on gastrointestinal tract mobility as compared to both AT and NT in a rodent model of GIT;
  • FIG. 6 depicts the absolute configuration of ( ⁇ )-E-10-OH-NT established by X-ray crystallographic analysis
  • FIG. 7 provides a graph demonstrating the superior antiallodynic efficacy of ( ⁇ )-E-10-OH-NT as compared to (+)-E-10-OH-NT, racemic ( ⁇ )-E-10-OH-NT and AT in a rodent model of non-nociceptive neuropathic pain;
  • FIG. 8 provides a graph demonstrating the antiallodynic efficacy of orally-administered ( ⁇ )-E-10-OH-NT as compared to that of amitriptyline in a rodent model of non-nociceptive neuropathic pain;
  • FIG. 9 provides a curve depicting the FCA and rotarod dose-response relationships for amitriptyline in a rodent model of nociceptive inflammatory pain
  • FIG. 10 provides a curve depicting the FCA and rotarod dose-response relationships for ( ⁇ )-E-10-OH-NT in a rodent model of nociceptive inflammatory pain;
  • FIG. 11 provides a graph demonstrating the dose-related antihyperalgesic activity of ( ⁇ )-E-10-OH-NT in a rodent model of nociceptive inflammatory pain
  • FIG. 12 provides a graph demonstrating the absence of substantial antihyperalgesic activity exhibited by (+)-E-10-OH-NT in a rodent model of nociceptive inflammatory pain
  • FIG. 13 provides a graph demonstrating the differential antihyperalgesic activity of the enantiomers of E-10-OH-NT in a rodent model of nociceptive inflammatory pain
  • FIG. 14 provides a graph comparing the antihyperalgesic activity of the enantiomers of E-10-OH-NT in a rodent model of nociceptive inflammatory pain
  • FIG. 15A provides a graph demonstrating the activity of amitriptyline (AT) in the rat Forced Swim Test model of depression;
  • FIG. 15B provides a graph demonstrating the activity of ( ⁇ )-E-10-OH-NT in the rat Forced Swim Test model of depression.
  • FIG. 15C provides a graph demonstrating that, at the dosages tested, (+)-E-10-OH-NT did not display statistically significant activity in the rat Forced Swim Test model of depression.
  • compositions comprising the E-geometrical isomers of the common major metabolite of the well-known tricyclic antidepressants amitriptyline (AT) and nortriptyline (NT): (S/R)-5-[3-Methylamino-prop-(E)-ylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (referred to herein as “E-10-OH-NT”), illustrated below:
  • the E-geometrical isomer comprises two enantiomers: (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT.
  • the E-10-OH-NT compound can be present as a non-racemic mixture enriched in the ( ⁇ ) enantiomer, as the substantially enantiomerically pure ( ⁇ ) enantiomer or as the enantiomerically pure ( ⁇ ) enantiomer.
  • the E-10-OH-NT compositions described herein comprise E-10-OH-NT that is substantially enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • the E-10-OH-NT compositions described herein comprise E-10-OH-NT that is enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • a composition is “enriched” in a particular enantiomer when that enantiomer is present in excess over the other enantiomer, i.e., when that enantiomer comprises more than 50% of the total E-10-OH-NT in the composition.
  • a composition that is enriched in a particular enantiomer will typically comprise at least about 60%, 70%, 80%, 90%, or even more, of the specific enantiomer.
  • the amount of enrichment of a particular enantiomer can be confirmed using conventional analytical methods routinely used by those skilled in the art, including NMR spectroscopy in the presence of chiral shift reagents, gas chromatographic analysis using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • a single enantiomer will be substantially free of the corresponding enantiomer.
  • substantially free of is meant that the composition comprises less than about 10% of the specified undesired enantiomer as established using conventional analytical methods routinely used by those of skill in the art, such as the methods mentioned above.
  • the amount of undesired enantiomer may be less than 10%, for example, less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or even less.
  • Enantiomerically enriched compositions that contain at least about 95% of a specified enantiomer are referred to herein as “substantially enantiomerically pure.” Compositions that contain at least about 99% of a specified enantiomer are referred to herein as “enantiomerically pure.”
  • the enantiomerically enriched E-10-OH-NT compositions described herein contain E-10-OH-NT that is approximately 60%, 70%, 80% or 90% pure in the ( ⁇ )-E-10-OH-NT. Stated another way, the ( ⁇ ) enantiomer is present at an enantiomeric excess (ee) in the range of about 60, 70, 80 or 90% ee. In some specific embodiments, the substantially enantiomerically pure E-10-OH-NT compositions described herein contain E-10-OH-NT that is approximately 95-98% pure in the ( ⁇ ) enantiomer; stated another way, the ( ⁇ )-E-10-OH-NT is present in an enantiomeric excess in the range of about 95-98% ee).
  • the enantiomerically pure E-10-OH-NT compositions described herein contain E-10-OH-NT that is approximately 99.0 to 100% pure in the ( ⁇ ) enantiomer; stated another way, the ( ⁇ )-E-10-OH-NT is present in an enantiomer excess in the range of about 99.0 to 100% ee).
  • E-10-OH-NT compositions in which the E-10-OH-NT is approximately 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 100% pure in the ( ⁇ ) enantiomer.
  • the enantiomerically pure E-10-OH-NT compositions described herein are intended to include enantiomerically pure ( ⁇ )-E-10-OH-NT of both biological and synthetic origins.
  • the enantiomerically pure E-10-OH-NT compositions described herein can contain from about 99% up to 100% enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • Embodiments of enantiomerically pure E-10-OH-NT compositions that are of biological origin (i.e., isolated from biological sources) and that therefore may contain 100% ( ⁇ )-E-10-OH-NT, are referred to herein as “biologically derived enantiomerically pure ( ⁇ )-E-10-OH-NT compositions.” Likewise, such E-10-OH-NT is referred to herein as “biologically derived enantiomerically pure ( ⁇ )-E-10-OH-NT.”
  • Embodiments of enantiomerically pure E-10-OH-NT compositions that are of synthetic origin, including compositions prepared ex vivo with the aid of chiral specific biocatalysts such as CYP2D6, and that therefore contain at least about 99%, but typically less than 100% ( ⁇ )-E-10-OH-NT are referred to herein as “synthetically derived enantiomerically pure ( ⁇ )-E-10-OH-NT compositions.” Likewise, such E-10-OH
  • the E-10-OH-NT can be present in the composition as the free base, or in the form of a salt, for example, an acid additional salt.
  • the E-10-OH-NT is present in the composition in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid and the like.
  • hydrohalide acids e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.
  • sulfuric acid nitric acid
  • phosphoric acid phosphoric acid
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenes
  • the E-10-OH-NT is present in the composition as an organic acid addition salt, for example, an acid addition salt formed with an organic acid selected from D-malic acid, L-malic acid and succinic acid.
  • the succinate salts of ( ⁇ )-E-10-OH-NT may have superior properties.
  • maleic acid has been previously associated with acute tubular necrosis toxicity (Everett et al., 1993). It is anticipated that the succinate salt will have superior ADME and toxicological safety properties than the maleate salt.
  • the ( ⁇ )-E-10-OH-NT constituting the composition is a succinate salt.
  • the E-10-OH-NT can be present in the composition in anhydrous form, or it can be in the form of a solvate and/or hydrate.
  • the degree and identity of solvating solvent will depend, in part, in the conditions used to synthesize and store the E-10-OH-NT compound.
  • the expressions “E-10-OH-NT,” ( ⁇ )-E-10-OH-NT, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT are intended to include all salt and/or solvate and/or hydrate forms of the compounds.
  • the ( ⁇ )-E-10-OH-NT compound can be synthesized or prepared using methods described in the literature, for example, racemic (+)-E-10-OH-NT can be synthesized as described in Bertrand et al., 1994 and Lassen et al., 1983, the disclosures of which are incorporated herein by reference.
  • Enantiomerically enriched compositions of ( ⁇ )-E-10-OH-NT can be prepared from such racemic mixtures by isolating the desired enantiomers using standard methods of chiral separation (see, e.g., Chiral Separation Techniques: A Practical Approach 2001).
  • FIG. 1A Another aspect of the disclosure provides means of synthesizing enantiomerically pure isomers of E-10-OH-NT using chiral specific synthesis methods.
  • An exemplary embodiment of methods useful for synthesizing enantiomerically pure (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT is illustrated in FIG. 1A .
  • the E-isomers of 5-( ⁇ -bromopropylidene)-10,11-dihydro-10-oxo-5H-dibenzo[a,b]-cycloheptene (compound 6) is reduced in the presence of a chiral-specific oxazaborolidine catalyst (illustrated as compounds S-10 and R-10).
  • the S-isomer of the catalyst (S-10) yields the ( ⁇ ) enantiomer of 5-( ⁇ -bromopropylidene)-10,11-dihydro-10-oxo-5H-dibenzo[a,b]-cycloheptene (compound ( ⁇ )-7), and the R-isomer (R-10) yields the (+)-enantiomer, (+)-7.
  • These intermediates can then be converted to their respective (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT products by reaction with methylamine.
  • the compound 6 starting material can be synthesized using methods described in the literature (see, e.g., Bertrand et al., 1994; Lassen et al., 1983, the disclosures of which are incorporated by reference). Alternatively, they can be synthesized as illustrated in FIG. 1A . Specific conditions for each illustrated step are provided in the Examples section.
  • FIG. 1A a specific chiral-specific oxazaborolidine catalyst is illustrated. Other chiral-specific oxazaborolidine catalysts could also be used. Specific representation examples are illustrated in FIG. 1B (in FIG. 1B , R is hydrogen or methyl) and described in Itsuno et al., 1983 (catalyst 10a), Corey et al., 1987 (catalyst 10b), Hong et al., 1994 (catalyst 10c), Quallich et al., 1993 (catalyst 10d) and Berenguer et al., 1994 (catalyst 10e).
  • the asymmetric induction achieved by the CBS reducing system is highly influenced by the variant group attached to the boron atom.
  • This group can be tuned to fit a particular substrate, although most commonly B-hydrogen or B-methyl is used.
  • the group attached to the boron atom directs the ketones to bind in such a way that there is minimal interaction between the B-R group and the small substituent of the ketone (for details regarding mechanistic studies, see Kim et al., 2006).
  • ( ⁇ )-E-10-OH-NT has a strong affinity for the norepinephrine (“NE”) transporter, and is a potent inhibitors of NE uptake.
  • ( ⁇ )-E-10-OH-NT also binds the serotonin transporter and inhibits uptake of 5HT, albeit with less potency than that observed for NE.
  • NE norepinephrine
  • AT, NT, desipramine, duloxetine, venlafaxine, citalopram, and simbalta are approved for the treatment of depression and have additional off label uses; and paroxetine and sertraline are approved for treatment of major depressive disorder, OCD, panic disorder, post traumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder, and also have additional off label uses.
  • E-10-OH-NT The ability of racemic E-10-OH-NT to cross the blood-brain barrier has been established in the literature (see, e.g., Nordin et al., 1987b). Accordingly, the E-10-OH-NT compositions described herein are expected to be useful to treat any disease and/or indication mediated, at least in part, by dysregulated NE reuptake. In some specific embodiments, it is expected that the E-10-OH-NT compositions described herein will be useful to treat many different diseases that respond to treatment with other NRI and SNRI agents, including, by way of example and not limitation, AT, NT, atomoxetine, reboxetine, and maprotiline.
  • NRI and SNRI agents including, by way of example and not limitation, AT, NT, atomoxetine, reboxetine, and maprotiline.
  • NRI and SNRI compounds include, but are not limited to, urinary disorders, including urinary incontinence; mood disorders such as depression and seasonal affective disorder (SAD); cognitive disorders such as dementia; psychotic disorders such as schizophrenia and mania; anxiety disorders; personality disorders such as ADHD; eating disorders such as anorexia nervosa and bulimia nervosa; chemical dependencies resulting from addictions to drugs or substances of abuse such as addictions to nicotine, alcohol, cocaine, heroin, phenobarbital and benzodiazepines; withdrawal syndromes; endocrine disorders such as hyperprolactinaemia; impulse disorders such as trichotillomania and kleptomania; tic disorders such as Tourette's syndrome; gastrointestinal tract disorders such as irritable bowel syndrome (IBS), ileus, gastroparesis, peptic ulcer, gastroesophageal reflux disease (GORD,
  • IBS irritable bowel syndrome
  • GORD gastroparesis
  • GORD gastroesophageal reflux disease
  • Pain is also thought to be mediated, at least in part, by dysregulated NE and/or 5-HT reuptake. Indeed, many NRI and/or SRI compounds are also used off-label to treat pain. Pain is generally understood to refer to the perception or condition of unpleasant sensory or emotional experience, which may or may not be associated with actual damage to tissues. It is generally understood to include two broad categories: acute and chronic (See, e.g., Buschmann et al., 2002; Jain, 2000) that is either of nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin.
  • nociceptive for example somatic or visceral
  • non-nociceptive for example neuropathic or sympathetic
  • the E-10-OH-NT compositions described herein are used to treat pain, including the various types pain discussed above.
  • such compositions comprise substantially enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • such compositions comprise enantiomerically pure ( ⁇ )-E-10-OH-NT.
  • racemic ( ⁇ )-E-10-OH-NT, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT exhibited similar affinities for the norepinephrine and serotonin transporters (Example 14), and the ( ⁇ ) and (+) isomers of E-10-OH-NT exhibited similar in vitro activity towards six different types of receptors and transporters, i.e., the norepinephrine transporter (Examples 4 and 14), serotonin transporter (Examples 4 and 14), dopamine transporter (Example 4), histaminergic receptor (Example 7), ⁇ adrenergic receptor (Example 9), and muscarinic receptors (Example 12), and also toward Cytochrome P450 functions (Example 10) and hERG ion channel (Example 11).
  • the E-10-OH-NT composition When used to treat various diseases or indications, the E-10-OH-NT composition will generally be administered in amounts effective to treat the particular disease or indication. As will be recognized by skilled artisans, what is understood to be “therapeutically effective” and providing therapeutic benefit oftentimes depends upon the specific disease or indication. Skilled artisans will be able to ascertain a therapeutically effective amount based upon long established criteria for the particular indication.
  • a “therapeutically effective” amount of a composition is an amount that eradicates or ameliorates the underlying disease or indication being treated and/or that eradicates or ameliorates one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, not withstanding that the patient may still be afflicted with the underlying disease or indication.
  • Therapeutic benefits also includes halting or slowing the progression of the disease or indication, regardless of whether improvement is realized.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the depression or the symptoms thereof, including, but not limited to, changes in mood, feeling of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, self-deprecation, insomnia, anorexia, weight loss, decreased energy and libido, and hormonal circadian rhythms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the anxiety disorder or one of the symptoms thereof including, but are not limited to, a fear of losing control of one's own actions, a sense of terror arising from no apparent reason, a dread of catastrophe, uneasiness, nervousness, nagging uncertainty about future events, headaches, fatigue, and sub-acute autonomic symptoms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the pain or the symptoms thereof including, but not limited to, shooting sensations, burning sensations, electrical sensations, aching, discomfort, soreness, tightness, stiffness, sleeplessness, numbness, and weakness.
  • AT and NT have been used in combination with other agents to treat various diseases and disorders.
  • AT has been used in combination with chlordiazepoxide to treat anxiety disorder and major depressive disorder, and has been used in combination with perphenazine to treat anxiety disorder, schizophrenia and major depressive disorder.
  • NT has been used in combination with budenoside to treat asthma. Given that AT, NT and the E-10-OH-NT compositions described herein inhibit uptake of NE and 5HT, it is expected that the E-10-OH-NT compositions described herein will also be useful in combination therapies.
  • the E-10-OH-NT compositions described herein may be used in combination with or as an adjunct to other agents.
  • the two agents may be administered in a single pharmaceutical compositor or they may be administered in separate pharmaceutical compositions.
  • the two components may be administered by the same route of administration or by a different route of administration.
  • the two components also may be administered simultaneously with each other or sequentially.
  • each component of the combination therapy may be administered separately but sufficiently closely in time to the administration of the other component as to provide the desired effect.
  • the combination therapy may include the administration of the E-10-OH-NT compositions described herein with other agents known to inhibit the reuptake of NE and 5HT.
  • the combination therapy may include the administration of the E-10-OH-NT compositions described herein with agents which do not inhibit the reuptake of NE and 5HT.
  • the E-10-OH-NT compositions described herein may be combined with other agents that inhibit reuptake of NE and/or 5HT, as well as, dual and triple monoamine uptake inhibits to treat depression.
  • the E-10-OH-NT compositions described herein also can be combined with a selective serotonin reuptake inhibitor (SSRI) such as, but not limited to, fluxetine, paroxetine, fluvoxamine, citaprolam, and sertraline to treat depression.
  • SSRI selective serotonin reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • Combination therapy for the treatment of depression may also involve a monoamine oxidase inhibitor (MAOIs), such as, but not limited to, tranylcypromine, phenelzine, and isocarboxazid.
  • MAOIs monoamine oxidase inhibitor
  • the combination therapy may involve a heterocyclic antidepressant such as, but not limited to, amoxapine, maprotiline, and trazodone, or another antidepressants such as, but not limited to venlafaxine, nefazodone, and mirtazapine.
  • a heterocyclic antidepressant such as, but not limited to, amoxapine, maprotiline, and trazodone
  • another antidepressants such as, but not limited to venlafaxine, nefazodone, and mirtazapine.
  • the combination therapy for the treatment of depression may involve the E-10-OH-NT compositions described herein and anti-anxiety agents, such as, but not limited to, chlordiazepoxide, or an anti-psychotic agents such as, but not limited to, perphenazine.
  • the E-10-OH-NT compositions described herein will be useful in combination therapies for the treatment of anxiety disorder, schizophrenia and asthma.
  • the E-10-OH-NT compositions described herein may be combined with anti-anxiety agents such as, but not limited to, chlordiazepoxide.
  • the E-10-OH-NT compositions described herein may be combined with an agent known to treat schizophrenia such as, but not limited to, perphenazine.
  • the E-10-OH-NT compositions described herein may be combined with agents known to treat asthma such as corticosteroids, including, but not limited to, budenoside.
  • E-10-OH-NT compositions described herein will be useful in combination therapy for the treatment of pain. Accordingly, the E-10-OH-NT compositions described herein can be combined with other analgesics, including but not limited to, cannabinoids and opioids.
  • cannabinoids include cannabinoids and opioids.
  • cannabinoids are available that may be suitable for use in combination therapy. Accordingly, the combination therapy may involve a cannabinoid that is selected from ⁇ 9 -tetrahydrocannabinol and cannabidiol, and mixtures thereof.
  • the E-10-OH-NT compositions described herein may be used in combination with at least one opioid.
  • opioids are available that may be suitable for use in combination therapy to treat pain.
  • the combination therapy may involve an opioid that is selected from, but not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonita
  • the opioid component of the combination therapy may further include one or more other active ingredients that may be conventionally employed in analgesic and/or cough-cold-antitussive combination products.
  • active ingredients include, for example, aspirin, acetaminophen, dextromethorphan, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/or guaifenesin.
  • Typical or conventional ingredients that may be included in the opioid component are described, for example, in the Physicians' Desk Reference, 1999, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the opioid component may further include one or more compounds that may be designed to enhance the analgesic potency of the opioid and/or to reduce analgesic tolerance development.
  • Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao et al., 1996), L-364,718 and other CCK antagonists (Dourish et al., 1988), NOS inhibitors (Bhargava et al., 1996), PKC inhibitors (Bilsky et al., 1996), and dynorphin antagonists or antisera (Nichols et al., 1997).
  • dextromethorphan or other NMDA antagonists Moo et al., 1996)
  • L-364,718 and other CCK antagonists Dourish et al., 1988
  • NOS inhibitors Bogava et al., 1996)
  • PKC inhibitors Boilsky et al., 1996)
  • the compounds described herein may be used with at least one non opioid analgesic, such as for example, diclofenac, a COX2 inhibitor, aspirin, acetaminophen, ibuprofen, naproxen, and the like, and mixtures thereof.
  • non opioid analgesic such as for example, diclofenac, a COX2 inhibitor, aspirin, acetaminophen, ibuprofen, naproxen, and the like, and mixtures thereof.
  • the combination therapy may involve an anti-inflammatory including, but not limited to, corticosteroids, aminoarylcarboxylic acid derivatives such as, but not limited to, etofenamate, meclofenamic acid, mefanamic acid, niflumic acid; arylacetic acid derivatives such as, but not limited to, acemetacin, amfenac cinmetacin, clopirac, diclofenac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, isozepac, lonazolac, metiazinic acid, oxametacine, proglumetacin, sulindac, tiaramide and tolmetin; arylbutyric acid derivatives such as, but not limited to, butibufen and fenbufen; arylcarboxylic acids such as, but not limited to, clid
  • the ( ⁇ )-E-10-OH-NT compound or pharmaceutical salts thereof described herein may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
  • the ( ⁇ )-E-10-OH-NT compound and/or compositions disclosed herein may be administered by any means that results in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient.
  • the compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
  • they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
  • the ( ⁇ )-E-10-OH-NT compound and/or compositions described herein may be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.
  • the ( ⁇ )-E-10-OH-NT compound and/or compositions may be formulated for oral administration, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the amount of active compound(s) in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention may be prepared so that an oral dosage unit form contains from about 0.1 to about 1000 mg of each active compound (and all combinations and subcombinations of ranges and specific concentrations therein).
  • the tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint
  • any material used in preparing any dosage unit form is preferably pharmaceutically pure and substantially non toxic in the amounts employed.
  • the ( ⁇ )-E-10-OH-NT compound and/or compositions may also be formulated for parental or intraperitoneal administration.
  • Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • a dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for administration by injection typically include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is preferably sterile and fluid to provide easy syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium stearate, sodium stearate, and gelatin.
  • Sterile injectable solutions may be prepared by incorporating the active compounds in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation may include vacuum drying and the freeze drying technique that yields a powder of the active ingredient, plus any additional desired ingredient from the previously sterile filtered solution thereof.
  • the ( ⁇ )-E-10-OH-NT compound and/or compositions will generally be administered in a therapeutically effective amount as described herein.
  • the amount of compound or composition administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
  • Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 0.1 or 1.0 or 2.0 or 2.5 or 5.0 or 10.0 or 20.0 or 25.0 or 50.0 or 75.0 or 100 mg/kg/day with an expected dose of about 5 mg/day to about 500 mg/day, but may be higher or lower, depending upon, among other factors, the particular disease or indication being treated the activity of the compound and/or composition, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds and/or compositions which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds and/or compositions may be administered once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the effective local concentration of active compounds and/or compositions may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • Initial dosages of the ( ⁇ )-E-10-OH-NT compound and/or compositions useful for the treatment of pain can be estimated from in vivo data, such as the animal models described in the Examples section. Additionally, initial dosages may be estimated from the data regarding the effective dosages of AT and NT for the treatment of the various disorders available in the art.
  • an effective dosage of ( ⁇ )-E-10-OH-NT for the treatment of pain in humans may be obtained by administering a dose of ( ⁇ )-E-10-OH-NT sufficient to achieve a plasma concentration similar to that achieved following the administration of 30 mg/kg, i.p. to rats.
  • the effective dose ( ⁇ )-E-OH-NT for the treatment of pain is the dosage required to achieve the plasma concentration achieved when ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.) is administered to rats.
  • Dosage amounts of ( ⁇ )-E-OH-NT for treating pain will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 0.1 or 1.0 or 2.0 or 2.5 or 5.0 or 10.0 or 20.0 or 25.0 or 50.0 or 75.0 or 100 mg/kg/day with an expected dose of about 5 mg/day to about 500 mg/day, but may be higher or lower. It is believed that oral doses of ( ⁇ )-E-10-OH-NT of between about 10 mg/day to about 20 or 25 or 30 or 35 or 40 or 45 or 50 or 60 or 70 or 80 or 90 or 95 or 100 or 150 or 200 or 250 or 300 mg/day will be effective in treating pain. Accordingly, some embodiments involve the administration of an oral dosage of ( ⁇ )-E-10-OH-NT between about 10 mg/day to about 100 mg/day.
  • an effective dosage of ( ⁇ )-E-10-OH-NT for the treatment of depression in humans may be obtained by administering a dose of ( ⁇ )-E-10-OH-NT sufficient to achieve a plasma concentration similar to that achieved following the administration of 30 mg/kg, i.p. to rats.
  • the effective dose ( ⁇ )-E-OH-NT for the treatment of depression is the dosage required to achieve the plasma concentration achieved when ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.) is administered to rats.
  • Dosage amounts of ( ⁇ )-E-OH-NT for treating depression will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 0.1 or 1.0 or 2.0 or 2.5 or 5.0 or 10.0 or 20.0 or 25.0 or 50.0 or 75.0 or 100 mg/kg/day with an expected dose of about 5 mg/day to about 500 mg/day, but may be higher or lower. It is believed that oral doses of ( ⁇ )-E-10-OH-NT of between about 10 mg/day to about 20 or 25 or 30 or 35 or 40 or 45 or 50 or 60 or 70 or 80 or 90 or 95 or 100 or 150 or 200 or 250 or 300 mg/day will be effective in treating depression. Accordingly, some embodiments involve the administration of an oral dosage of ( ⁇ )-E-10-OH-NT between about 10 mg/day to about 100 mg/day.
  • depression can be treated with a plasma level of the enantiomers of E-10-OH-NT of between about 140 nM and about 220 nM. Based on the reported pharmacokinetic properties of ( ⁇ )-E-10-OH-NT, it is believed that depression can be treated with a plasma level of ( ⁇ )-E-10-OH-NT between about 140 nM and 220 nM and that these plasma levels can be achieved by administering between about 30 mg/day to about 35 or 40 or 45 or 50 or 55 or 60 or 65 or 70 or 75 or 80 or 85 or 90 or 95 or 100 or 150 or 200 or 250 or 300 mg/day.
  • certain embodiments involve the administration of ( ⁇ )-E-10-OH-NT at the daily dose required to achieve a plasma level of between about 140 nM and 220 nM.
  • the dosage of ( ⁇ )-E-10-OH-NT is between about 30 mg/day and about 100 mg/day.
  • the proper dosage of the combined agents will be readily ascertainable by a skilled artisan based on the above disclosed dosages for ( ⁇ )-E-10-OH-NT and long established criteria for the particular indication.
  • a cannabinoid, opioid and/or other agent is used in combination with the E-10-OH-NT compositions described herein
  • typically the dosage may range from about 0.01 to about 100 mg/kg/day of the cannabinoid, opioid and/or other active compound and about 0.001 to about 100 mg/kg/day of the E-10-OH-NT composition described herein.
  • the dosage may be about 0.1 to about 10 mg/kg/day of the cannabinoid, opioid and/or other active compound and about 0.01 to about 10 mg/kg/day of the E-10-OH-NT compositions described herein and in other embodiments, the daily dosage may be about 1.0 mg of the cannabinoid, opioid and/or other active compound and about 0.1 mg of the E-10-OH-NT compositions described herein.
  • the E-10-OH-NT compositions described herein are combined with a cannabinoid compound (e.g., ⁇ 9 -tetrahydrocannabinol or cannabidiol), an opioid compound (e.g., morphine) and/or an other agent and the combination is administered orally, generally the dosage may range from about 15 to about 200 mg of the cannabinoid, opioid and/or other agent, and about 0.1 to about 4 mg of the E-10-OH-NT compositions described herein.
  • a cannabinoid compound e.g., ⁇ 9 -tetrahydrocannabinol or cannabidiol
  • an opioid compound e.g., morphine
  • the dosage may range from about 15 to about 200 mg of the cannabinoid, opioid and/or other agent, and about 0.1 to about 4 mg of the E-10-OH-NT compositions described herein.
  • H 1 histaminergic antagonism might induce weight gain
  • prior studies have amply demonstrated that H 1 histaminergic receptor antagonism increases feeding in rodents whereas H 2 histaminergic antagonism does not (Sakata et al., 1988; Fukagawa et al., 1989).
  • depletion of neuronal histamine increases feeding (Menon et al., 1971; Sakai et al., 1995).
  • H 1 knockout mice are relatively resistant to the anorectic actions of leptin, and are prone to obesity when placed on high-fat diets (Masaki et al., 2001a, Masaki et al., 2001b).
  • H 1 histaminergic receptors modulate feeding behavior via a leptin-dependent mechanism.
  • the study by Kroeze and collaborators demonstrated that H 1 histaminergic receptor affinity is significantly correlated with short-term weight gain when a large number of typical and atypical anti-psychotic drugs are examined. These results imply that anti-psychotic drugs with relatively high H 1 histaminergic receptor affinities are likely to induce short-term weight gain.
  • ( ⁇ )-E-10-OH-NT An additional advantageous property of ( ⁇ )-E-10-OH-NT is its reduced inhibition of key drug metabolizing enzymes.
  • the metabolic conversion of drugs generally is enzymatic.
  • the enzyme systems involved in the biotransformation of drugs are mainly localized in the liver, although every tissue examined has some metabolic activity. Following nonparenteral administration of a drug, a significant portion of the dose may be metabolically inactivated in either the liver or the intestines before it reaches the systemic circulation. This first-pass metabolism significantly limits the oral bioavailability of highly metabolized drugs. (Benet et al., 1995).
  • the cytochrome P450 enzyme family is the major catalyst of drug biotransformation reactions.
  • cytochrome P 450 enzymes catalyzes a wide variety of oxidative and reductive reactions and has activity towards a chemically diverse group of substrates.
  • Key cytochrome P 450 enzymes include CYP2D6 and CYP2C19. Alterations in the activity of these enzymes, either due to polymorphism or through inhibition, leads to undesirable clinical consequences (see Ingelman-Sundberg et al., 1999).
  • AT and NT are associated with cardiotoxicity, including arrhythmias.
  • the blocking of the cardiac K + channel (Ikr) has been linked to drug-induced long QT syndrome (LQT), which can lead to Torsades de Pointes, a life threatening form of arrhythmia, and subsequent ventricular fibrillation (see, Pearlstein et al., 2003).
  • LQT drug-induced long QT syndrome
  • TCAs tricyclic antidepressants
  • TCAs such as imipramine and AT inhibit hERG channels at clinically relevant concentrations (Witchel et al., 2002).
  • a further advantage of ( ⁇ )-E-10-OH-NT, as explained in detail in Example 11, is that it has a significantly lower activity at the hERG channel than AT and NT. Based on this result, it is expected that treatments utilizing ( ⁇ )-E-10-OH-NT will yield reduced risk of QT prolongation, Torsade de Pointes and other arrhythmic-related adverse effects compared to AT and NT.
  • the tricyclic antidepressants also produce blood pressure effects due to their interaction with the ⁇ 1 adrenergic receptors.
  • the blockade of ⁇ 1 adrenergic receptors which occurs notably with doxepin, nefazodone, AT and clomipramine, is responsible for orthostatic hypotension, dizziness and reflex tachycardia (Hamon & Bourgoin, 2006).
  • An advantage of ( ⁇ )-E-10-OH-NT, as described in detail in Example 9, is its weaker affinity at the ⁇ 1a and ⁇ 1a adrenergic receptors compared to AT and NT. Based on these in vitro data, it is expected that ( ⁇ )-E-10-OH-NT will be less likely to produce orthostatic hypotension, dizziness and reflex tachycardia.
  • the ⁇ 2 adrenoceptor antagonists RX821002 [2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) at doses up to 3 mg/kg when administered by itself subcutaneously did not produce significant inhibition of acetic acid-induced abdominal constriction (pain assay).
  • the ⁇ 2 adrenoceptor agonist clonidine yielded a dose-dependent inhibition of abdominal constriction over the dose range 0.01 up to 1.0 mg/kg (s.c.) and at the highest dose level, it totally abolished the abdominal constriction response, thus affording 100% protection against the algogenic stimulus.
  • ( ⁇ )-E-10-OH-NT exhibits significantly lower affinity than AT and NT for the adrenergic receptors ⁇ 2a , ⁇ 2b , and ⁇ 2c .
  • ( ⁇ )-E-10-OH-NT will be superior to AT and/or NT with respect to potential side effects: the analgesic effects of ( ⁇ )-E-10-OH-NT may not be offset by an interaction with ⁇ 2 adrenergic receptors, while the analgesic effects of AT and NT may be reduced by interaction with ⁇ 2 adrenergic receptors.
  • kits The ( ⁇ )-E-10-OH-NT compounds and/or pharmaceutical salts thereof described herein may be assembled in the form of kits.
  • the kit provides the compounds(s) and reagents to prepare a composition for administration.
  • the composition may be in a dry or lyophilized from, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • the kit may contain a device for administration or for dispensing the compositions, including, but not limited to, syringe, pipette, transdermal patch or inhalant.
  • kits may include other therapeutic agents for use in conjunction with the compounds described herein.
  • the therapeutic agents may be provided in a separate form, or mixed with the compounds described herein.
  • Kits will include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information.
  • the instructions may be in any suitable format; including, but not limited to, printed matter, videotape, computer readable disk, or optical disk.
  • (+)-E-5-( ⁇ -bromopropylidene)-10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]-cycloheptene, compound (+)-7 A solution of compound 6 (2.00 g, 6.11 mmol, 1.00 eq) in tetrahydrofuran (25 mL) was added drop wise to a solution of borane-dimethyl sulfide complex (0.326 mL, 3.67 mmol, 0.60 eq) and (7 ⁇ R)-3-methyl-1,1-diphenylperhydro-3-bora-2-oxapyrrolizine (1.02 g, 3.67 mmol, 0.60 eq) in tetrahydrofuran (75 mL) at ⁇ 20° C.
  • (+)-E-10-OH-NT compound (+)-8.
  • (+)-E-10-OH-NT was synthesized by heating a solution of (+)-7 (0.95 g, 2.6 mmol, 1.00 eq) and methyl amine (40% by weight in water, 7.00 mL, 81 mmol, 31 eq) in acetonitrile (10 mL) at 60° C. for 16 hours in a pressure vessel. The reaction was concentrated to near dryness and purified by flash silica gel column chromatography using a 5-9% methanol/chloroform gradient (plus 1% ammonium hydroxide) to give 650 mg of a light orange foam in 90% yield.
  • the impure free base (650 mg, 2.33 mmol, 1.00 eq) was dissolved in acetonitrile and filtered to remove any insoluble particles. The filtrate was concentrated, dissolved in acetonitrile (15 mL) and maleic acid (324 mg, 2.79 mmol, 1.20 eq) was added. The mixture was stirred for 30 minutes and a solid precipitated out. The mixture was concentrated, dried and recrystallized from isopropanol (100 mL) to give 535 mg of a white crystalline solid, i.e., (+)-E-10-OH-NT as the maleate salt.
  • the impure free base was dissolved in dichloromethane, filtered to remove any insoluble particles, concentrated and dried to give 1.9 g of a light yellow foam in quantitative yield.
  • the free base (1.37 g, 4.9 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL) and maleic acid (0.654 g, 5.64 mmol, 1.15 eq) is added. The mixture was stirred for 60 minutes and a solid precipitated out.
  • the succinate salt of ( ⁇ )-E-10-OH-NT was prepared by dissolving 9.15 g of ( ⁇ )-8 (free base, 88.6% E isomer, 11.4% Z isomer) in isopropanol (40 mL) and adding a solution of succinic acid (4.25 g, 1.10 eq) in isopropanol (90 mL). A minor amount of product crystallized out of solution after 2 days, so the mixture was concentrated to a 20 mL mixture and the resulting solid was filtered to give 11 g of succinate salt of ( ⁇ )-E-10-OH-NT which was 94% E isomer and 6% Z isomer.
  • the solid was recrystallized twice from acetonitrile (400 mL and 300 mL) to give 6.78 g light orange crystals (99.2% E isomer, 0.8% Z isomer).
  • the resultant succinate salt is crystalline and non-hydroscopic in nature, and has a higher solubility in saline (18 mg/ml) than the maleate salt (4.4 mg/ml).
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT are Potent Selective Inhibitors of Norepinephrine Reuptake
  • the binding affinities of AT, NT, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for the norepinephrine (NE) transporter, the serotonin (5HT) transporter and dopamine (DA) transporter were determined in competitive binding assays with radiolabeled ligands.
  • NE transporter binding assay [ 3 H]nisoxetine (1.0 nM) was incubated with various concentrations of test compounds for 2 hours at 4° C. with membranes prepared from Chinese hamster ovary cells (CHO) cells heterologously expressing the cloned human NE transporter (hNET). Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of binding that occurred in the presence of 1.0 ⁇ M desipramine.
  • the K i values of the various test compounds were determined using standard methods.
  • [ 3 H]imipramine (2.0 nM) was incubated in the presence of various concentrations of test compounds for 1 hour at 22° C. with membranes prepared from CHO cells heterologously expressing the human serotonin transporter (hSERT). Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of binding that occurred in the pressure at 10 ⁇ M imipramine.
  • the K i values of the various test compounds were determined using standard methods.
  • the ability of AT, NT (+)-E-10-OH-NT, and ( ⁇ )-E-10-OH-NT to inhibit uptake of NE, 5HT and DA was also assessed.
  • the IC 50 values in NE uptake was determined by measuring the inhibition of the incorporation of [ 3 H]-norepinephrine into rat hypothalamus synaptosomes upon incubation for 20 minutes at 37° C.
  • the IC 50 values in 5HT uptake was determined by measuring the inhibition of the incorporation of [ 3 H]-5HT into rat brain synaptosomes upon incubation for 15 min at 37° C.
  • the IC 50 values in DA uptake was determined by measuring the inhibition of the incorporation of [ 3 H]-DA into rat striatum synaptosomes upon incubation for 15 min at 37° C.
  • binding affinities for the various transporters are provided in Table 1, below.
  • K i values are in nanomolar. Percentages are the percent inhibition of binding observed with 10 ⁇ M test compound.
  • IC 50 values are in nanomolar. Percentages are the percent inhibition of uptake observed with 10 ⁇ M test compound.
  • affinities of (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for the NE transporter were approximately equal to that of AT, and within about 10-fold that of NT. Similar results were observed for the IC 50 values for the inhibition of NE uptake. The IC 50 values for the inhibition of NE uptake are lower than those previously reported for racemic E-10-OH-NT. (See Hyttel, 1980 which reported an IC 50 of 130 nM for NE uptake assay in mouse atria.)
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for the NE transporter were comparable to that of AT, the affinities of (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for the 5HT transporter like the affinity of NT are significantly greater than the affinity of AT. Similar results were observed for the IC 50 values for the inhibition of 5HT uptake. Based on these results, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT like NT exhibit selectively for the NE transporter versus the 5HT transporter.
  • racemic (+)-E-10-OH-NT also exhibits selective affinities for the NE and 5HT transporters that are approximately equipotent to those of the (+) and ( ⁇ ) enantiomers.
  • paw pressure thresholds were determined before and at specified times after drug treatment.
  • Each trial started with a von Frey force of 2 grams delivered to the right hindpaw for approximately 1-2 seconds and then the left hindpaw. If there was no withdrawal response, the next higher force was delivered. If there was a response, the next lower force was delivered. This procedure was performed until no response was made at the highest force (15 grams) or until four stimuli were administered following the initial response.
  • Each test group contained 8 animals.
  • the sham-operated control group which were operated on but not subject to nerve ligation, contained 4 animals. All animals were tested at 60 minutes, and 240 minutes, post-administration of test compounds.
  • results The results are illustrated in FIG. 4 .
  • ( ⁇ )-E-10-OH-NT was administered as either the maleate or succinate salt.
  • AT was administered as the hydrochloride salt. Dosage amounts are based on the amount of free base.
  • the antiallodynic activity of ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.) was statistically significant over that observed for the vehicle-treated control group (vehicle-treated, L5 SNL rats), and comparable to that of AT (30 mg/kg, i.p.).
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT Bind to the H 1 Histaminergic Receptor with Weak Affinity
  • affinities of AT, NT, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for the H 1 histaminergic receptor were assessed in a competitive binding assay.
  • [ 3 H]pyrilamine (3 nM) was incubated with various concentrations of test compound for 1 hour at 22° C. with membranes prepared from human embryonic kidney (HEK-293) cells heterologously expressing the cloned human H 1 histaminergic receptor. Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of binding that occurred in the presence of 1.0 ⁇ M unlabeled pyrilamine.
  • the rat rotarod assay is commonly used to assess sedation associated with chemical drugs.
  • Time course experiments were performed with AT (30 mg/kg, i.p.) NT (30 mg/kg, i.p.) and ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.).
  • the rotarod was set in motion at a constant speed and the rats were placed onto the individual rotating drums of the apparatus. Once the rats were in position, the timers were set to zero and the rotarod switched to accelerating mode. The rotarod accelerated from 4 to 40 rpm over a five-minute interval. The timers automatically turned off when the rats fell from the rotating drum, recording a latency to fall in seconds.
  • the rats had 3 training sessions, separated by at least 15 minutes, prior to drug administration.
  • the performance score was recorded in seconds for each interval.
  • the baseline rotarod performance score was the latency to fall off the rotarod on the third training session.
  • Baselines must have been greater than or equal to 60 seconds duration for the rat to be included in the experiment. Animals were tested at 30, 60 and 120 minutes following administration of test compound.
  • results The results are shown in FIG. 2 .
  • ( ⁇ )-E-10-OH-NT was administered as either maleate or succinate salt.
  • NT and AT were administered as hydrochloride salts. The dosage amounts are based on the amount of free base. Peak deficits in rotarod performance were observed at 30 minutes in rats treated with AT or NT. The magnitude of the effects of AT and NT on rotarod performance were similar, with peak deficits of 51 ⁇ 20% and a 60 ⁇ 14%, respectively. In stark contrast, no impairment of performance was observed in rats treated with ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.).
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT have Low Affinity for Alpha Adrenergic Receptors
  • affinities of AT, NT, (+)-E-10-OH-NT and ( ⁇ )-E-OH-NT for the ⁇ 1a , ⁇ 2b , ⁇ 2a , ⁇ 2b , and ⁇ 2c adrenergic receptors was tested.
  • Affinity for the ⁇ 1a adrenergic receptor was tested using membranes prepared from rat salivary gland. [ 3 H]Prazocine (0.06 nM) was incubated in the presence of various concentrations of test compounds with the membranes for 1 hour at 22° C. Nonspecific binding was determined in the presence of 10 ⁇ M phentolamine. Bound radioactivity was determined by scintillation spectroscopy.
  • Affinity for the ⁇ 1b adrenergic receptor was tested using membranes prepared from Chinese hamster ovary (CHO) cells heterologously expressing the cloned human receptor that were incubated with [ 3 H]prazocine (0.15 nM) in the presence of various concentrations of test compounds for 1 hour at 22° C. Nonspecific binding was determined in the presence of 10 ⁇ M phentolamine. Bound radioactivity was determined by scintillation spectroscopy.
  • Affinity for the ⁇ 2a adrenergic receptor was tested using CHO cells heterologously expressing the cloned human receptor that were incubated with [ 3 H]RX821002 (1.0 nM) in the presence of various concentrations of test compounds for 1 hour at 22° C. Nonspecific binding was determined in the presence of 100 ⁇ M ( ⁇ )-epinephrine. Bound radioactivity was determined by scintillation spectroscopy.
  • Affinity for the ⁇ 2b adrenergic receptor was tested using CHO cells heterologously expressing the cloned human receptor that were incubated with [ 3 H]RX821002 (2.5 nM) in the presence of various concentrations of test compounds for 1 hour at 22° C. Nonspecific binding was determined in the presence of 100 ⁇ M ( ⁇ )-epinephrine. Bound radioactivity was determined by scintillation spectroscopy.
  • Affinity for the ⁇ 2c adrenergic receptor was tested using CHO cells heterologously expressing the cloned human receptor with [ 3 H]RX821002 (2.0 nM) in the presence of various concentrations of test compounds for 1 hour at 22° C. Nonspecific binding was determined in the presence of 100 ⁇ M ( ⁇ )-epinephrine. Bound radioactivity was determined by scintillation spectroscopy.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT exhibit significantly lower affinity than AT and NT for all adrenergic receptors listed, particularly at the ⁇ 2 receptors. Accordingly, it is expected that the analgesic effects of (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT may not be offset by their interaction with the ⁇ 2 adrenergic receptors while the analgesic responses of AT and NT may be offset by their interaction with the ⁇ 2 adrenergic receptors.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT do not Inhibit Cytochrome P450 Function
  • CYP2C19 activity was measured using dibezylflourescein (DBF) as substrate.
  • DBF dibezylflourescein
  • the source of enzyme was microsomes containing human recombinant CYP2C19 obtained from BD Biosciences (San Jose, Calif.). Conversion of DBF to fluorescein was measured using a PerkinElmer Fusion with a 485 nm excitation filter and a 535 nm emission filter.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT surprisingly demonstrated a significant and unexpected decrease in the inhibitory activity at the polymorphic cytochrome P450 isoenzymes CYP2D6 and CYP2C19 as compared to both AT and NT.
  • This reduction in inhibitory activity for the (+) and ( ⁇ ) enantiomers of E-10-OH-NT is expected to lead to a reduction in undesirable clinical consequences when compared to AT and NT and allow for use of (+)- and ( ⁇ )-E-10-OH-NT in patients taking medications contraindicated for use with AT and NT.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT Inhibit the hERG Channel to a Lesser Extent than AT and NT
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT significantly lower activity is observed with (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT than AT and NT. Based on these results, it is expected that treatments utilizing (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT could yield a reduced risk of QT prolongation and other arrhythmic-related adverse effects as compared to treatments with AT and NT.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT have Lower Affinities for Muscarinic Receptors than AT and NT
  • affinities of AT, NT (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT for muscarinic receptors M 1 , M 2 , M 3 , M 4 and M 5 were determined with membranes prepared from CHO cells heterologously expressing the cloned human muscarinic receptors M 1 , M 2 , M 3 , M 4 and M 5 .
  • membranes and radiolabelled ligand were incubated with various concentrations of test compounds for 1 hour at 22° C. Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of bound radioligand in the presence of 1.0 ⁇ M atropine.
  • Radioligand for the M 1 receptor was [ 3 H]pirenzepine (2 nM).
  • Radioligand for the M 2 receptor was [ 3 H]AF-DX384 (2 nM).
  • Radioligand for the M 3 , M 4 , and M 5 receptors was [ 3 H]4-DAMP.
  • (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT exhibited approximately equal affinities, and significantly lower affinities than both AT and NT.
  • Gastrointestinal transit was determined by removing the entire length of the small intestine and measuring how far the leading edge of the charcoal meal traveled in the small intestine.
  • the percent GIT was determined by the following formula:
  • %GIT [distance to charcoal leading edge (cm)/length of small intestine (cm) ⁇ 100]
  • [ 3 H]imipramine (2.0 nM) was incubated in the presence of various concentrations of test compounds for 1 hour at 22° C. with membranes prepared from CHO cells heterologously expressing the human serotonin transporter (hSERT). Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of binding that occurred in the pressure at 10 ⁇ M imipramine.
  • the K i values of the various test compounds were determined using standard methods.
  • racemic (+)-E-10-OH-NT for the norepinephrine transporter was comparable to that observed for the purified enantiomers, (+)-E-10-OH-NT and ( ⁇ )-E-10-OH-NT, which were approximately equal to one another.
  • binding affinity of racemic (+)-E-10-OH-NT for the serotonin transporter was also comparable to that observed for both of the purified (+)-E-10-OH-NT and the ( ⁇ )-E-10-OH-NT.
  • the chamber was positioned on top of a mesh screen so that von Frey monofilaments could be presented to the plantar surface of both hindpaws.
  • Measurement of tactile sensitivity for each hindpaw were obtained using the up/down method (Dixon, 1980) with seven Frey monofilaments (0.4, 1, 2, 4, 6, 8 and 15 grams).
  • Each trial started with a von Frey force of 2 grams delivered to the right hindpaw for approximately 1-2 seconds and then the left hindpaw. If there was no withdrawal response, the next higher force was delivered. If there was a response, the next lower force was delivered. This procedure was performed until no response was made at the highest force (15 grams) or until four stimuli were administered following the initial response.
  • Each test group contained 8 animals.
  • the sham-operated control group which were operated on but not subject to nerve ligation, contained 4 animals. All animals were tested at 60 minutes post-administration of test compounds.
  • results The results are illustrated in FIG. 7 .
  • the antiallodynic activity of ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.) was greater than that observed for the vehicle-treated control group (vehicle-treated, L5 SNL rats) (“VEH”) and comparable to that of AT (30 mg/kg, i.p.).
  • the antiallodynic activity of ( ⁇ )-E-10-OH-NT (30 mg/kg, i.p.) was also greater than that observed for both (I)-E-10-OH-NT (30 mg/kg, ip) and ( ⁇ )-E-10-OH-NT (30 mg/kg, ip).
  • the activities of the racemic mixture and the (+) enantiomer were both comparable to that of the vehicle-only control (“VEH”).
  • results The results are illustrated in FIG. 8 .
  • the antiallodynic activity of ( ⁇ )-E-10-OH-NT (30 mg/kg, p.o. and 60 mg/kg p.o.) was greater than that observed for the vehicle-treated control and comparable to that of AT (30 mg/kg, i.p.). Dosage amounts are based on the amount of free base administered.
  • AT and ( ⁇ )-E-10-OH-NT displayed similar potencies and efficacies for the reversal of mechanical hyperalgesia in 24 h FCA-treated rats.
  • IP a high level of antihyperalgesic activity
  • % AH antihyperalgesic activity
  • Impairment of rotarod performance in rats was used to assess the degree of sedation produced by ( ⁇ )-E-10-OH-NT and AT.
  • AT dose dependently decreased rotarod performance with an ED 50 value of 27 mg/kg IP and a maximal impairment of 96% observed at a dose of 100 mg/kg IP ( FIG. 9 ).
  • 30 mg/kg IP ( ⁇ )-E-10-OH-NT only produced a 5% impairment of rotarod performance.
  • the estimated ED 50 value for ( ⁇ )-E-10-OH-NT impairment of rotarod performance was 120 mg/kg IP ( FIG. 10 ).
  • paw pressure thresholds were determined before and at specified times after drug treatment.
  • Results The results are illustrated in FIG. 11 and demonstrate that orally-administered ( ⁇ )-E-10-OH-NT provides significant activity in the rat FCA-induced hyperalgesia assay.
  • (+)-E-10-OH NT had similar antihyperalgesic potency and efficacy as ( ⁇ )-E-10-OH NT in 24 h FCA-treated rats.
  • a time course experiment was performed with 30 mg/kg IP of (+)-E-10-OH NT.
  • rats were administered either vehicle or 30 mg/kg IP of (+)-E-10-OH-NT (administered the maleate or succinate salt; the dosage amount is based on the amount of free base administered).
  • Paw pressure thresholds were determined 1, 2, or 4 hours after administration using the methods disclosed in Examples 5 and 18. Vehicle-treated rats were tested at 1 hour post-treatment. (+)-E-10-OH NT was not antihyperalgesic at any time point tested ( FIG. 12 ).
  • (+)-E-10-OH NT was not active at doses up to 30 mg/kg IP. Accordingly, rats were treated with sterile water vehicle, 30, or 60 mg/kg IP twenty-four hours after administration of FCA. Rats were tested for hyperalgesia 1 hour after treatment with vehicle or (+)-E-10-OH NT.
  • mice Male Sprague-Dawley rats (approximately 200 g) are placed in a tank of room temperature water for a fifteen minute practice swim. Every five seconds during the first five minutes of the practice swim, the rats are rated as immobile (floating with motion needed to keep head above the water), swimming (movement across the swim), or climbing (actively trying to climb out of the tank of water, upward directed movements of the forepaws). The percentage of time the rats spent in each of these responses is calculated.
  • the rats are treated with vehicle or test compound and placed in the tank for a 5 minute swim. As was the case with the practice swim, the rats are rated as immobile, swimming, or climbing during the test swim and the percentage of time spent in each of these responses is calculated. The data are analyzed by one-way ANOVA with post-hoc analysis to compare the behavioral response after vehicle treatment to the behavioral response after drug treatment for each of the three behavioral responses. The level of significance is set at p ⁇ 0.05.
  • ( ⁇ )-E-10-OH-NT produced similar magnitudes of effects as amitriptyline, demonstrating a significant decrease in immobility after treatment with 30 mg/kg IP (47% decrease) and significant increases in swimming in rats treated with 10 (64% increase) or 30 mg/kg IP (108%).
  • ( ⁇ )-E-10-OH NT did not alter the amount of time spent climbing ( FIG. 15B ).
  • (+)-E-10-OH-NT was not active in the forced swim test at doses up to 30 mg/kg IP ( FIG. 15C ).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Addiction (AREA)
  • Agronomy & Crop Science (AREA)
  • Diabetes (AREA)
  • Psychology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
US12/107,742 2007-04-30 2008-04-22 Compositions of (-)-e-10-oh-nt and methods for their synthesis and use Abandoned US20080275131A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/107,742 US20080275131A1 (en) 2007-04-30 2008-04-22 Compositions of (-)-e-10-oh-nt and methods for their synthesis and use
US13/427,744 US20120178815A1 (en) 2007-04-30 2012-03-22 Compositions of (-)-E-10-OH-NT and Methods for Their Synthesis and Use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US91510307P 2007-04-30 2007-04-30
US2781408P 2008-02-11 2008-02-11
US2812208P 2008-02-12 2008-02-12
US12/107,742 US20080275131A1 (en) 2007-04-30 2008-04-22 Compositions of (-)-e-10-oh-nt and methods for their synthesis and use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/427,744 Division US20120178815A1 (en) 2007-04-30 2012-03-22 Compositions of (-)-E-10-OH-NT and Methods for Their Synthesis and Use

Publications (1)

Publication Number Publication Date
US20080275131A1 true US20080275131A1 (en) 2008-11-06

Family

ID=39926044

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/107,742 Abandoned US20080275131A1 (en) 2007-04-30 2008-04-22 Compositions of (-)-e-10-oh-nt and methods for their synthesis and use
US13/427,744 Abandoned US20120178815A1 (en) 2007-04-30 2012-03-22 Compositions of (-)-E-10-OH-NT and Methods for Their Synthesis and Use

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/427,744 Abandoned US20120178815A1 (en) 2007-04-30 2012-03-22 Compositions of (-)-E-10-OH-NT and Methods for Their Synthesis and Use

Country Status (14)

Country Link
US (2) US20080275131A1 (ru)
EP (1) EP2152074A4 (ru)
JP (1) JP2010526075A (ru)
KR (1) KR20100019985A (ru)
CN (1) CN101720186A (ru)
AU (1) AU2008245836A1 (ru)
BR (1) BRPI0810773A2 (ru)
CA (1) CA2685395A1 (ru)
IL (1) IL201766A0 (ru)
MX (1) MX2009011858A (ru)
NO (1) NO20093448L (ru)
NZ (1) NZ581391A (ru)
RU (1) RU2469715C2 (ru)
WO (1) WO2008134325A1 (ru)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090233958A1 (en) * 2008-02-19 2009-09-17 Adolor Corporation (+)-beloxepin and methods for its synthesis and use
US20090233957A1 (en) * 2008-02-19 2009-09-17 Adolor Corporation (-)-beloxepin and methods for its synthesis and use
US20100173927A1 (en) * 2008-02-19 2010-07-08 Adolor Corporation Beloxepin and analogs for the treatment of pain

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2540151B1 (es) * 2013-10-11 2016-02-29 Farmalider S.A. Composición farmacéutica de ibuprofeno y tramadol para uso oftálmico
KR20180035219A (ko) * 2015-07-15 2018-04-05 테라네수스 뇌의 헤미채널을 차단하기 위한 아미트리프틸린의 용도 및 이의 생체 내 효과 증진 방법
CN110143944A (zh) * 2019-05-08 2019-08-20 上海升华医药科技有限公司 一种手性二苯并[b,e]硫杂*-11-醇的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552548A (en) * 1992-05-14 1996-09-03 Pfizer Inc. Enantioselective oxazaborolidine catalysts
US20040242594A1 (en) * 2001-11-17 2004-12-02 Dan Peters Prodrugs of antidepressants and their use for treating depressions
US7041835B2 (en) * 2001-08-24 2006-05-09 Dor Pharmaceutical, Inc. (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3547998A (en) * 1968-08-09 1970-12-15 Lilly Co Eli Intermediate and process for the preparation of nortriptyline
US4593031A (en) * 1982-03-22 1986-06-03 Sandoz, Inc. Method of treating depression
JPH10510540A (ja) * 1994-12-12 1998-10-13 オメロス メディカル システムズ，インコーポレーテッド 灌注用溶液並びに疼痛、炎症及びけいれんの抑制法
EP1007041A4 (en) * 1997-04-11 2001-03-07 Lilly Co Eli COMPOSITION FOR TREATING PAIN
DE60035232T2 (de) * 1999-07-01 2008-02-14 Pharmacia & Upjohn Co. Llc, Kalamazoo (S,S)-Reboxetin zur Behandlung von chronischem Müdigkeits-Syndrom
DE60233414D1 (de) * 2001-07-09 2009-10-01 Combinatorx Inc Kombinationen für die behandlung entzündlicher erkrankungen
GB0219024D0 (en) * 2002-08-15 2002-09-25 Pfizer Ltd Synergistic combinations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552548A (en) * 1992-05-14 1996-09-03 Pfizer Inc. Enantioselective oxazaborolidine catalysts
US7041835B2 (en) * 2001-08-24 2006-05-09 Dor Pharmaceutical, Inc. (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor
US20040242594A1 (en) * 2001-11-17 2004-12-02 Dan Peters Prodrugs of antidepressants and their use for treating depressions

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090233958A1 (en) * 2008-02-19 2009-09-17 Adolor Corporation (+)-beloxepin and methods for its synthesis and use
US20090233957A1 (en) * 2008-02-19 2009-09-17 Adolor Corporation (-)-beloxepin and methods for its synthesis and use
US20100173927A1 (en) * 2008-02-19 2010-07-08 Adolor Corporation Beloxepin and analogs for the treatment of pain
US7829576B2 (en) 2008-02-19 2010-11-09 Adolor Corporation Beloxepin and analogs for the treatment of pain
US20110105552A1 (en) * 2008-02-19 2011-05-05 Adolor Corporation Beloxepin and analogs for the treatment of pain

Also Published As

Publication number Publication date
CA2685395A1 (en) 2008-11-06
JP2010526075A (ja) 2010-07-29
NO20093448L (no) 2010-02-01
CN101720186A (zh) 2010-06-02
US20120178815A1 (en) 2012-07-12
KR20100019985A (ko) 2010-02-19
MX2009011858A (es) 2010-01-14
NZ581391A (en) 2012-06-29
IL201766A0 (en) 2010-06-16
RU2469715C2 (ru) 2012-12-20
EP2152074A1 (en) 2010-02-17
AU2008245836A1 (en) 2008-11-06
BRPI0810773A2 (pt) 2014-10-07
EP2152074A4 (en) 2011-07-27
RU2009144121A (ru) 2011-06-10
WO2008134325A1 (en) 2008-11-06

Similar Documents

Publication Publication Date Title
US20120178815A1 (en) Compositions of (-)-E-10-OH-NT and Methods for Their Synthesis and Use
US20010036949A1 (en) Pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal
US20050070552A1 (en) Ion channel modulating activity I
US20040082555A1 (en) Use of gaba, inverse agonists in combination with nicotine receptor partial agonist, estrogen, selective estrogen modulators, or vitamin E for the treatment of cognitive disorders
US11246860B2 (en) 5-HT2A agonists for use in treatment of depression
NO317178B1 (no) Anvendelse av (+) norcisaprid for fremstilling av medikamenter samt farmasoytisk preparat og enhetsdoseform omfattende forbindelsen
SK22004A3 (sk) Farmaceutická kompozícia na moduláciu cholínergnej funkcie a použitie kombinácie NRPA zlúčeniny a antiemetického/antinauzeózneho činidla na výrobu liečiva
WO2009105507A2 (en) Beloxepin, its enantiomers, and analogs thereof for the treatment of pain
JP2011512414A5 (ru)
US20130296414A1 (en) 1-Phenyl-2-Dimethylaminomethyl Cyclohexane Compounds And Therapies For Depressive Symptoms, Pain and Incontinence
US20090233957A1 (en) (-)-beloxepin and methods for its synthesis and use
NZ526108A (en) Use of optically pure (-) norcisapride in the treatment of bulimia
US20090233958A1 (en) (+)-beloxepin and methods for its synthesis and use
US7829576B2 (en) Beloxepin and analogs for the treatment of pain
Le Bourdonnec et al. BELOXEPIN AND METHODS FOR ITS SYNTHESIS AND USE
MXPA02006374A (es) Combinacion de trimebutina con un opioide analgesico.
AU2003220743B2 (en) Use of optically pure (+)-norcisapride for treating apnea, bulimia and other disorders
NZ739883A (en) 5-ht2c receptor agonists and compositions and methods of use
NZ739883B2 (en) 5-ht2c receptor agonists and compositions and methods of use
US20120095073A1 (en) Ion channel modulating activity ii

Legal Events

Date Code Title Description
AS Assignment

Owner name: ADOLOR CORPORATION, PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LE BOURDONNEC, BERTRAND;DOLLE, ROLAND E.;REEL/FRAME:021258/0343

Effective date: 20080708

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT, CAN

Free format text: SECURITY AGREEMENT;ASSIGNORS:CUBIST PHARMACEUTICALS, INC.;ADOLOR CORPORATION;CALIXA THERAPEUTICS, INC.;AND OTHERS;REEL/FRAME:029339/0669

Effective date: 20121120

AS Assignment

Owner name: ADOLOR CORPORATION, PENNSYLVANIA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT;REEL/FRAME:036180/0070

Effective date: 20150707

Owner name: CUBIST PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT;REEL/FRAME:036180/0070

Effective date: 20150707

Owner name: CALIXA THERAPEUTICS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT;REEL/FRAME:036180/0070

Effective date: 20150707